The Second Study of Cytisinicline for Smoking Cessation in Adult Smokers (ORCA-3) trial compared a smoking cessation pharmacotherapy with placebo after 12 weeks of treatment. Continuous smoking abstinence rates with cytisinicline were nearly six times better than placebo through 24 weeks. Based on the positive results, which were published in April, the manufacturer submitted a new drug application for cytisinicline in late June.
“This is a new formulation of an old drug that has been used as a smoking cessation medication for decades in Europe,” said lead author Nancy Rigotti, MD, Director for the Tobacco Research and Treatment Center and Professor of Medicine at Harvard Medical School. “If it’s approved, it will be the first new medication for smoking cessation since 2006. That’s a very long time to go without something new to offer patients.”
Cytisinicline is a reformulation of cytisine, a naturally occurring plant-based alkaloid that binds selectively to α4β2 nicotinic acetylcholine receptors to reduce nicotine cravings and withdrawal symptoms while limiting nicotine’s self-reward effects. Side effects and six-times-per-day dosing have limited uptake in older formulations.
Current smoking cessation medications include nicotine replacement, bupropion, and varenicline, but long-term smoking cessation rates are modest. Side effects can deter appropriate use, and many tobacco users have tried some or all without success.
“Cytisinicline’s method of action resembles that of varenicline, the single best agent we now have, but it had fewer side effects in clinical trials. We need a drug that is as good as or better than varenicline, with fewer side effects, and doesn’t have the name Chantix (or varenicline) because of patient concerns about neuropsychiatric effects, even though those were found to be inaccurate,” Dr. Rigotti said.
The prospect of a new smoking cessation drug is alluring to both patients and clinicians.
“What’s exciting is broadening our field of view on how we might be able to gain control of this problem pharmacologically for more people,” said Frank Leone, MD, MS, Director of Comprehensive Smoking Treatment Programs and Professor of Medicine at the University of Pennsylvania, and Chair of CHEST’s Tobacco/Vaping Work Group. “People tend to think of smoking cessation medications as interchangeable, but that’s like calling all blood pressure medications interchangeable or all asthma medicines [interchangeable]. They have the same goal, but the mechanisms may be different. That’s where the value of cytisinicline is going to come in.”
ORCA-3 compared cytisinicline 3 mg three times daily for 12 weeks, cytisinicline 3 mg three times daily for six weeks followed by placebo for six weeks, and placebo for 12 weeks in adults who smoked. All participants also received behavioral support from trained counselors.
The primary outcome was biochemically confirmed smoking abstinence during the last four weeks of the six-week and 12-week treatments. Secondary outcomes included smoking abstinence through 24 weeks.
A total of 792 participants who smoked a mean of 20 cigarettes daily were randomized to six weeks of treatment (263), 12 weeks of treatment (264), or placebo (265). The mean age was 52, and 55% were women. The study was conducted at 22 sites in the United States.
For the six-week treatment group, smoking cessation at the end of treatment was higher at weeks 3 through 6 for cytisinicline with 14.8% abstinence vs 6.0% for placebo (OR, 2.9; 95% CI, 1.5-5.6; P < .001). For the 12-week treatment group, 30.3% achieved abstinence during weeks 9 through 12 vs 9.4% for placebo (OR, 4.4; 95% CI, 2.6-7.3; P < .001).
For the secondary outcome, cytisinicline also showed higher likelihood for smoking abstinence through 24 weeks in both groups vs placebo. Continuous abstinence rates for the six-week treatment group was 6.8% for cytisinicline vs 1.1% for placebo from weeks 3 to 24 (OR, 6.3; 95% CI, 1.8-34.6; P < .001). Continuous abstinence for the 12-week treatment group was 20.5% for cytisinicline vs 4.2% for placebo for weeks 9 to 24 (OR, 5.8; 95% CI, 2.9-12.4; P < .001).
Treatment-emergent adverse events were similar across the three groups and most commonly included insomnia, abnormal dreams, nausea, and headache. Discontinuation because of adverse events was similar in all groups.
“Once the drug is available commercially, second-level research questions like how to use cytisinicline in combination with older drugs or in concert with acute nicotine replacement therapy are going to be of importance,” Dr. Leone said. “Additionally, if treatment is extended, will results get better?”
